Artículos (Medicina)

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Correction to: Early Stepdown From Echinocandin to Fluconazole Treatment in Candidemia: A Post Hoc Analysis of Three Cohort Studies
(Oxford University Press, 2022-05-23) Moreno-García, E.; Puerta-Alcalde, Pedro; Gariup, G.; Fernández-Ruiz, M.; López-Cortés, Luis E.; Cuervo, G.; Garnacho Montero, José; Rodríguez-Baño, Jesús; García-Vidal, C.; Medicina; European Union (UE); Gobierno de España; Instituto de Salud Carlos III
There are no clear criteria for antifungal de-escalation after initial empirical treatments. We hypothesized that early de-escalation (ED) (within 5 days) to fluconazole is safe in fluconazole-susceptible candidemia with controlled source of infection. (excerpt from the original text)
Sepsis, a call for inclusion in the work plan of the European Center for Disease Prevention and Control
(Springer, 2023-08-24) Giamarellos-Bourboulis, Evangelos J.; Zinkernagel, Annelies S.; De Robertis, Edoardo; Azoulay, Élie; De Luca, Daniele; Rodríguez-Baño, Jesús; European Society for Pediatric and Neonatal Intensive Care (ESPNIC); Medicina; Hellenic Institute for the Study of Sepsis
Sepsis is a devastating condition resulting from our bodies’ dysregulated immune system response to infections, which can lead to organ failure, death, or sometimes life-long disability. (section)
Revisiting the personal protective equipment components of transmission-based precautions for the prevention of COVID-19 and other respiratory virus infections in healthcare
(European Centre for Disease Prevention and Control, 2023-08-10) Plachouras, Diamantis; Kacelnik, Oliver; Rodríguez-Baño, Jesús; Birgand, Gabriel; Borg, Michael A.; Kristensen, Brian; Monnet, Dominique L.; Medicina
Standard and transmission-based precautions are essential elements of infection prevention and control (IPC) practices. Transmission-based precautions are applied in addition to standard precautions in patients suspected or confirmed to be infected or colonised with certain microorganisms. There are three types of transmission-based precautions, depending on the transmission route: contact, droplet and airborne precautions. Each type of precautions has implications for the use of personal protective equipment (PPE) and for administrative and engineering control measures such as the placement of the patient, staff cohorting and training and environmental cleaning. Contact precautions include the application of gloves and gowns, droplet precautions require the use of medical face masks, and airborne precautions require the placement of the patient in an airborne precaution isolation room and the use of a well-fitted respirator by the staff. Sometimes, transmission-based precautions are combined to ensure that multiple modes of transmission are addressed. For respiratory infections, two concepts of transmission through the air have been distinguished: short-range droplet transmission and long-range aerosol transmission. In the current transmission-based precautions, most respiratory viruses were considered as being transmitted primarily through large droplets and only in exceptional situations by aerosols, resulting in the widespread application of droplet precautions such as the use of a medical face masks, rather than precautions against airborne transmission. The COVID-19 pandemic highlighted a potential limitation of the underpinning theory and application of transmission-based precautions as used during the past decades.
Predictors of clinical evolution of SARS-CoV-2 infection in hematological patients: A systematic review and meta-analysis
(Wiley, 2022-10-13) Carrara, Elena; Razzaboni, Elisa; Azzini, Anna Maria; De Rui, Maria Elena; Pinho Guedes, Mariana Nunes; Gorska, Anna; Rodríguez-Baño, Jesús; Tacconelli, Evelina; Medicina; European Union
Main aim of this systematic review is to quantify the risk and identify predictors of clinical evolution of SARS-CoV-2 in hematological patients compared to different control populations. Two independent reviewers screened the literature assessing clinical outcomes of SARS-CoV-2 infection in adult patients with active hematological malignancies published up to June 2021. Primary outcome was COVID-19 related mortality, secondary outcomes were hospital and intensive-care admission, mechanical ventilation (MV), and thromboembolic events. Variables related to study setting, baseline patients' demographic, comorbidities, underlying hematological disease, ongoing chemotherapy, COVID-19 presentation, and treatments were extracted. A total of 67 studies including 10,061 hematological patients and 111,143 controls were included. Most of the studies were retrospective cohorts (51 studies, 76%) and only 19 (13%) provided data for a control group. A significant increased risk of clinical progression in the hematological population compared to the controls was found in terms of COVID-19 related mortality (OR, 2.12; 95% CI, 1.77–2.54), hospitalization (OR, 1.98; 95% CI, 1.15–3.43), intensive-care admission (OR, 1.77; 95% CI, 1.38–2.26), and MV (OR, 2.17; 95% CI, 1.71–2.75). The risk remained significantly higher in the subgroup analysis comparing hematological patients versus solid cancer. Meta-regression analysis of uncontrolled studies showed that older age, male sex, and hypertension were significantly related to worse clinical outcomes of COVID-19 in hematological population. Older age and hypertension were found to be associated also to thromboembolic events. In conclusion, hematological patients have a higher risk of COVID-19 clinical progression compared to both the general population and to patients with solid cancer.
Incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infection in European hospitals: the COMBACTE-NET ARTHR-IS multi-centre study
(Elsevier, 2023-10-04) Espíndola, Reinaldo; Vella, Venanzio; Benito, Natividad; Mur, Isabel; Tedeschi, Sara; Zamparini, Eleonora; Rodríguez-Baño, Jesús; Toro López, María Dolores del; Medicina; European Union (UE); Gobierno de España; Instituto de Salud Carlos III; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG); Innovative Medicines Initiative Joint Undertaking
Background: The aim of this study was to estimate the incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infections (SA-PJI) after primary hip and knee arthroplasty in European centres. Methods: This study was conducted in patients who underwent primary hip and knee arthroplasty in 19 European hospitals between 2014 and 2016. The global incidence of PJI and SA-PJI was calculated. The associated disease burden was measured indirectly as infection-related mortality plus loss of function. For healthcare utilization, number and duration of hospitalizations, number and type of surgical procedures, duration of antibiotic treatments, and number of outpatient visits were collected. Subgroup and regression analyses were used to evaluate the impact of SA-PJI on healthcare utilization, controlling for confounding variables. Results: The incidence of PJI caused by any micro-organism was 1.41%, and 0.40% for SA-PJI. Among SA-PJI, 20.7% were due to MRSA with substantial regional differences, and were more frequent in partial hip arthroplasty (PHA). Related deaths and loss of function occurred in 7.0% and 10.2% of SA-PJI cases, respectively, and were higher in patients with PHA. Compared with patients without PJI, patients with SA-PJI had a mean of 1.4 more readmissions, 25.1 more days of hospitalization, underwent 1.8 more surgical procedures, and had 5.4 more outpatient visits, controlling for confounding variables. Healthcare utilization was higher in patients who failed surgical treatment of SA-PJI. Conclusions: This study confirmed that the SA-PJI burden is high, especially in PHA, and provided a solid basis for planning interventions to prevent SA-PJI.
Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia
(Wiley, 2023-01-21) Terzić, Vida; Levoyer, Léa; Figarella, Mélanie; Bigagli, Elisabetta; Mercier, Noémie; De Gastines, Lucie; Rodríguez-Baño, Jesús; c4c safety group; Medicina
Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk–benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.
How European Research Projects Can Support Vaccination Strategies: The Case of the ORCHESTRA Project for SARS-CoV-2
(MDPI, 2023-08-14) Azzini, Anna Maria; Canziani, Lorenzo Maria; Davis, Ruth Joanna; Mirandola, Massimo; Hoelscher, Michael; Meyer, Laurence; Rodríguez-Baño, Jesús; Tacconelli, Evelina; Medicina; European Union
ORCHESTRA (“Connecting European Cohorts to Increase Common and Effective Response To SARS-CoV-2 Pandemic”) is an EU-funded project which aims to help rapidly advance the knowledge related to the prevention of the SARS-CoV-2 infection and the management of COVID-19 and its long-term sequelae. Here, we describe the early results of this project, focusing on the strengths of multiple, international, historical and prospective cohort studies and highlighting those results which are of potential relevance for vaccination strategies, such as the necessity of a vaccine booster dose after a primary vaccination course in hematologic cancer patients and in solid organ transplant recipients to elicit a higher antibody titer, and the protective effect of vaccination on severe COVID-19 clinical manifestation and on the emergence of post-COVID-19 conditions. Valuable data regarding epidemiological variations, risk factors of SARS-CoV-2 infection and its sequelae, and vaccination efficacy in different subpopulations can support further defining public health vaccination policies.
Epidemiology, Clinical Features, and Antimicrobial Resistance of Invasive Escherichia Coli Disease in Patients Admitted in Tertiary Care Hospitals
(Oxford University Press, 2023-01-27) Doua, Joachim; Geurtsen, Jeroen; Rodríguez-Baño, Jesús; Cornely, Oliver A.; Go, Oscar; Gomila-Grange, Aina; Sarnecki, Michal; Medicina; Janssen Research and Development, LLC
Background: Invasive Escherichia coli disease (IED), including bloodstream infection, sepsis, and septic shock, can lead to high hospitalization and mortality rates. This multinational study describes the clinical profile of patients with IED in tertiary care hospitals. Methods: We applied clinical criteria of systemic inflammatory response syndrome (SIRS), sepsis, or septic shock to patients hospitalized with culture-confirmed E coli from urine or a presumed sterile site. We assessed a proposed clinical case definition against physician diagnoses. Results: Most patients with IED (N = 902) were adults aged ≥60 years (76.5%); 51.9%, 25.1%, and 23.0% of cases were community-acquired (CA), hospital-acquired (HA), and healthcare-associated (HCA), respectively. The urinary tract was the most common source of infection (52.3%). Systemic inflammatory response syndrome, sepsis, and septic shock were identified in 77.4%, 65.3%, and 14.1% of patients, respectively. Patients >60 years were more likely to exhibit organ dysfunction than those ≤60 years; this trend was not observed for SIRS. The case-fatality rate (CFR) was 20.0% (60–75 years, 21.5%; ≥75 years, 22.2%), with an increase across IED acquisition settings (HA, 28.3%; HCA, 21.7%; CA, 15.2%). Noticeably, 77.8% of patients initiated antibiotic use on the day of culture sample collection. A total of 65.6% and 40.8% of E coli isolates were resistant to ≥1 agent in ≥1 or ≥2 drug class(es). A 96.1% agreement was seen between the proposed clinical case definition and physician's diagnoses of IED. Conclusions: This study contributes valuable, real-world data about IED severity. An accepted case definition could promote timely and accurate diagnosis of IED and inform the development of novel preventative strategies.
Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial
(Springer, 2024-01-10) Trøseid, Marius; Arribas, José R.; Assoumou, Lambert; Holten, Aleksander Rygh; Poissy, Julien; Terzić, Vida; Rodríguez-Baño, Jesús; Costagliola, Dominique; Medicina; European Union (UE); CAPNET; Klinbeforsk
Background: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies.
Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): a phase 3, randomized, double-blind, placebo-controlled trial
(Elsevier, 2024-03) Hites, Maya; Larrañaga Lapique, Eva; Massonnaud, Clément R.; Belhadi, Drifa; Jamard, Simon; Goehringer, François; Rodríguez-Baño, Jesús; Ader, Florence; Medicina; European Commission (EC); Astra-Zeneca; DIM One Health Ile-de-France
We read with great interest the recent article by Kamboj et al., in which they described the risk of developing moderate to severe Coronavirus Disease 2019 (COVID-19) in patients with hematological malignancies receiving tixagevimab-cilgavimab (T-C) during a period in which the dominant circulating variants of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) were resistant to T-C.1 The authors highlight the ongoing need to urgently address the mAb treatment gap, particularly for immunocompromised patients. The unmet need is further highlighted by the DisCoVeRy Phase 3, adaptive, multicenter European, randomized, double-blind, superiority trial that evaluated the efficacy and safety of intravenous T-C in SARS-CoV-2 antigenic positive patients (i.e. those with a high SARSCoV-2 viral load) hospitalized with COVID-19 and followed-up to day 90. (abstract)
External validation of the predictive ability of Charson, SOFA, Pitt, INCREMENT-ESBL and bloodstream infection mortality Risk for 30-day-mortality in bacteraemia using the PROBAC cohort data
(Taylor & Francis, 2025-07-09) Rosa-Riestra, Sandra; Gutiérrez Gutiérrez, Belén; López-Hernández, Inmaculada; Pérez-Rodríguez, María Teresa; Goikoetxea Aguirre, Josune; Plata, Antonio; López-Cortés, Luis E.; Rodríguez-Baño, Jesús; Medicina; Gobierno de España; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Introduction: The development of predictive mortality scores for bacteraemia is fundamental for identifying patients in whom increasing our management efforts. However, it is necessary to assess the validity of the results obtained when they are applied to new cohorts. Methods: We evaluated the ability of different scales (Charlson, also age-adjusted Charlson and updated Charlson, SOFA, Pitt, INCREMENT-ESBL and BSIMRS) to predict 30-day mortality in bacteraemia through the AUROC and calibration plots. The scales were applied to specific patient from PROBAC cohort (prospective, multicentre with bacteraemia of any aetiology) according to the population in which the scale was originally developed. We also applied the recently developed PROBAC score (this time applied to the entire PROBAC cohort, rather than only to patients who did not die within 48 h of blood culture collection as in the original development of the scale). Results: After applying Charlson, age-adjusted Charlson, updated Charlson, SOFA, Pitt and PROBAC to the entire PROBAC cohort, we obtained AUROC values: 0.60 (95% CI: 0.58-0.62); 0.62 (95% CI: 0.60-0.64); 0.60 (95% CI: 0.58-0.62); 0.69 (95% CI: 0.66-0.71); 0.71 (95% CI: 0.69-0.82) and 0.80 (95% CI: 0.79-0.81), respectively. INCREMENT-ESBL was applied only to gram negative bacteraemia yielding 0.81 (95% CI: 0.79-0.82) and BSIMRS to gram negative bacteraemia who received adequate empirical antibiotic yielding 0.72 (95% CI: 0.70-0.75).
Mortality impact of further delays in active targeted antibiotic therapy in bacteraemic patients that did not receive initial active empiric treatment: Results from the prospective, multicentre cohort PROBAC
(Elsevier Science Ltd, 2024-08) Rosa Riestra, Sandra de la; Martínez Pérez-Crespo, Pedro María; Pérez Rodríguez, María Teresa; Sousa, Adrián; Goikoetxea, Josune; Reguera Iglesias, José María; Arminanzas, Carlos; López-Hernández, Inmaculada; López-Cortés, Luis E.; Rodríguez-Baño, Jesús; Medicina; Gobierno de España; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); PROBAC
Objectives: The early initiation of the empirical antibiotic treatment and its impact on mortality in pa- tients with bacteraemia has been extensively studied. However, information on the impact of precocity of the targeted antibiotic treatment is scarce. We aimed to study the impact of further delay in active antibiotic therapy on 30-day mortality among patients with bloodstream infection who had not received appropriate empirical therapy. Design: We worked with PROBAC cohort (prospective and compound by patients from 26 different Span- ish hospitals). We selected a total of 1703 patients, who survived to day 2 without having received any active antibiotic therapy against the causative pathogen. Results: The 30-day mortality was 14% (238 patients). The adjusted odds of mortality increased for every day of delay, from 1.53 (95% confidence interval (CI) 1.13-2.08) for day 3 or after to 11.38 (95% CI 7.95- 16.38) for day 6 or after. Conclusion: We concluded that among patients who had not received active treatment within the first 2 days of blood culture collection, additional delays in active targeted therapy were associated with in- creased mortality. These results emphasize the importance of active interventions in the management of patients with bloodstream infections.
Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort
(Elsevier, 2023-08) Gentilotti, Elisa; Górska, Anna; Tami, Adriana; Gusinow, Roy; Mirandola, Massimo; Rodríguez-Baño, Jesús; Hara, Gabriel Levy; ORCHESTRA Study Group; Medicina
Background Lack of specificdefinitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%),respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively). Interpretation Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials.
Case report: Analysis of phage therapy failure in a patient with a Pseudomonas aeruginosa prosthetic vascular graft infection
(Frontiers Media SA, 2023-05-19) Blasco, Lucía; López-Hernández, Inmaculada; Rodríguez-Fernández, Miguel; Pérez-Florido, Javier; Casimiro-Soriguer, Carlos S.; Djebara, Sarah; Merabishvili, Maya; Pirnay, Jean Paul; Rodríguez-Baño, Jesús; Tomás, María; López-Cortés, Luis E.; Medicina; Microbiología; Instituto de Biomedicina de Sevilla (IBIS)
Clinical case of a patient with a Pseudomonas aeruginosa multidrug-resistant prosthetic vascular graft infection which was treated with a cocktail of phages (PT07, 14/01, and PNM) in combination with ceftazidime-avibactam (CZA). After the application of the phage treatment and in absence of antimicrobial therapy, a new P. aeruginosa bloodstream infection (BSI) with a septic residual limb metastasis occurred, now involving a wild-type strain being susceptible to ß-lactams and quinolones. Clinical strains were analyzed by microbiology and whole genome sequencing techniques. In relation with phage administration, the clinical isolates of P. aeruginosa before phage therapy (HE2011471) and post phage therapy (HE2105886) showed a clonal relationship but with important genomic changes which could be involved in the resistance to this therapy. Finally, phenotypic studies showed a decrease in Minimum Inhibitory Concentration (MIC) to ß-lactams and quinolones as well as an increase of the biofilm production and phage resistant mutants in the clinical isolate of P. aeruginosa post phage therapy.
Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial
(Elsevier, 2023-09-11) Pittet, Laure F.; Moore, Cecilia L.; McDonald, Ellie; Barry, Simone; Bonten, Marc; Campbell, John; Rodríguez-Baño, Jesús; Curtis, Nigel; Ríos-Villegas, María José; BRACE Trial Consortium Group; Medicina
Background Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8x105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a f irst episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore.
Recurrent Clostridioides difficile infections in solid organ transplant recipients: The international CALIPSO study
(W B Saunders Company Ltd, 2024-10-05) Tiseo, Giusy; Yahav, Dafna; Atamna, Alaa; Avni, Tomer; Causse, Manuel; Pérez-Nadales, Elena; Rodríguez-Baño, Jesús; Falcone, Marco; Medicina
Objective: To evaluate the risk of recurrent Clostridioides difficile infection (CDI) in solid-organ transplant (SOT) recipients. Methods: Retrospective multicenter study including SOT recipients with a first CDI episode in the year after transplantation (Jan 2017-June 2020). The primary outcome measure was recurrence, defined as a new CDI ≤56 days from the first episode. A competing risk analysis was performed using the sub-distribution hazard model multivariable analysis. Results: 191 SOT recipients were included: 101 (52.9%) were kidney, 66 (34.6%) liver, 11 (5.8%) lung, 8 (4.2%) simultaneous pancreas-kidney, 4 (2.1%) heart and 1 (0.5%) pancreas alone recipients. Treatment for the first CDI were: vancomycin (n = 114,59.7%), vancomycin+metronidazole (n = 39,20.4%), metronidazole (n = 26,13.6%), fidaxomicin (n = 9,4.7%), 3 patients did not receive any therapy. After the first CDI, 17/191 (8.9%) patients died within 56-day mortality without having a recurrence, while 23/191 (12%) patients had a recurrence. Among patients with recurrent CDI, 56-day mortality rate was 30.4% (7/23 patients). On mul tivariable analysis, severe CDI (sHR4.01, 95% CI 1.77–9.08, p < .001) and metronidazole monotherapy (sHR 3.65, 95% CI 1.64–8.14, p = .001) were factors independently associated with recurrence. Conclusions: Metronidazole monotherapy is associated with increased risk of recurrent CDI in SOT re cipients. Therapeutic strategies aimed to reduce the risk of recurrence should be implemented in this setting.
Predicting the next pandemic: VACCELERATE ranking of the World Health Organization’s Blueprint for Action to Prevent Epidemics
(Elsevier Science Ltd., 2023-12-17) Salmanton-García, Jon; Wipfler, Pauline; Leckler, Janina; Nauclér, Pontus; Mallon, Patrick W.; Bruijning-Verhagen, Patricia C.J.L.; Schmitt, Heinz-Joseph; Bethe, Ulrich; Olesen, Ole F.; Stewart, Fiona A.; Albus, Kerstin; Cornely, Oliver A.; Rodríguez-Baño, Jesús; VACCELERATE Consortium; Medicina; Unión Europea
Introduction: The World Health Organization (WHO)’s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of trig gering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS- CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks.
Effectiveness of oral step-down therapy and early oral switch for bloodstream infections caused by Enterobacterales: A post hoc emulation trial of the SIMPLIFY trial
(Elsevier Science Ltd., 2025) Rando, Emanuele; Delgado Valverde, María Mercedes; Goikoetxea Aguirre, Josune; Guío Carrión, Laura; Blanco Vidal, María José; Barrios Andrés, José Luis; Retamar Gentil, Pilar; Rodríguez-Baño, Jesús; López-Cortés, Luis E.; Medicina; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades; Gobierno de España
Objectives We investigated the effectiveness of early oral switch for treating Enterobacterales bloodstream infection (BSI) by performing a post hoc emulation trial of the SIMPLIFY trial. Methods We conducted a post hoc analysis of a randomized controlled trial. We specified the target trial characteristics selecting patients who achieved clinical stability on day 5. We categorized patients into those who switched on day 5 and those who continued intravenously. The primary outcome was clinical cure at the test of cure. We set a propensity score for being switched on day 5 to reduce confounding. We ran simple, not-propensity-adjusted, and propensity-adjusted logistic regression models to ascertain the association of switch on day 5 with clinical cure. Results Among 303 patients who achieved clinical stability on day 5, 110 (36.3%) were switched orally on day 5, and 193 (63.7%) were kept intravenously. We detected no difference in clinical cure between those switched on day 5 and those continued intravenously (risk ratios 1.04, 95% confidence intervals [CI] 0.98-1.10). Propensity-adjusted analysis did not show an association between day 5 switch and clinical cure (OR 2.10, 95% CI 0.96-7.41). Conclusion Oral step-down therapy on day 5 was not associated with worse clinical cure for Enterobacterales BSI.
International and regional spread of carbapenem-resistant Klebsiella pneumoniae in Europe
(Nature Publishing Group; Nature Portfolio, 2024-06-14) Budia Silva, Mabel; Kostyanev, Tomislav; Ayala Montano, Stefany; Bravo Ferrer Acosta, José; García Castillo, María; Cantón, Rafael; Goossens, Herman; Rodríguez-Baño, Jesús; Grundmann, Hajo; Reuter, Sandra; Medicina; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Carbapenem-resistant Klebsiella pneumoniae (CRKP) are of particular concern due to the spread of antibiotic resistance genes associated with mobile genetic elements. In this study, we collected 687 carbapenem-resistant strains recovered among clinical samples from 41 hospitals in nine Southern European countries (2016-2018). We identified 11 major clonal lineages, with most isolates belonging to the high-risk clones ST258/512, ST101, ST11, and ST307. blaKPC-like was the most prevalent carbapenemase-encoding gene (46%), with blaOXA-48 present in 39% of isolates. Through the combination and comparison of this EURECA collection with the previous EuSCAPE collection (2013-2014), we investigated the spread of high-risk clones circulating in Europe exhibiting regional differences. We particularly found blaKPC-like ST258/512 in Greece, Italy, and Spain, blaOXA-48 ST101 in Serbia and Romania, blaNDM ST11 in Greece, and blaOXA-48-like ST14 in Türkiye. Genomic surveillance across Europe thus provides crucial insights for local risk mapping and informs necessary adaptions for implementation of control strategies.
Genomic virulence markers are associated with severe outcomes in patients with Pseudomonas aeruginosa bloodstream infection
(Springer Nature, 2024-12-11) Valik, John Karlsson; Giske, Christian G.; Hasan, Badrul; Gozalo Margüello, Mónica; Martínez-Martínez, Luis; Mueller Premru, Manica; Rodríguez-Baño, Jesús; Nauclér, Pontus; Medicina
Background Pseudomonas aeruginosa (PA) bloodstream infection (BSI) is a common healthcare-associated complication linked to antimicrobial resistance and high mortality. Ongoing clinical trials are exploring novel anti-virulence agents, yet studies on how bacterial virulence affects PA infection outcomes is conflicting and data from real-world clinical populations is limited. Methods We studied a multicentre cohort of 773 adult patients with PA BSI consecutively collected during 7-years from sites in Europe and Australia. Comprehensive clinical data and whole-genome sequencing of all bacterial strains were obtained. Results Based on the virulence genotype, we identify several virulence clusters, each showing varying proportions of multidrug-resistant phenotypes. Genes tied to biofilm synthesis and epidemic clones ST175 and ST235 are associated with mortality, while the type III secretion system is associated with septic shock. Adding genomic biomarkers to machine learning models based on clinical data indicates improved prediction of severe outcomes in PA BSI patients. Conclusions These findings suggest that virulence markers provide prognostic information with potential applications in guiding adjuvant sepsis treatments.

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